Quaternary ammonium salts of tertiary-aminoalkyl substituted phenylacetonitriles



Patented Sept. 4, 1951 QUATERNARY AMMONIUM SALTS F 'TERTIARY-AMINOALKYL' SUBSTITUTED PHENYLACETONITRILES Arlo Wayne Ruddy, Albany, N. Y., assignor to Sterling Drug Inc., New York, N. Y., a corporation of Delaware No Drawing. Application January 27, 1949,

Serial N 0;73330 1 This invention relates to quaternary ammonium salts of the general formula.

....Y\ I N=B wherein R is an alkyl or alkenyl radical of 4-6 carbon atoms or a 5-6 membered cycloalkyl radical, R. is an alkyl radical of 1-6 carbon atoms or a 15 Claims. (01. Mil-$93) lower aralkyl radical, such as benzyl, which can bear inert nuclear substitutents such as halo, alkoxy or lower alkyl; Y is an ethylene radical which may be substituted by alkyl groups, N=B is a dialkylamino, piperidino, pyrrolidino and morpholino group, and X is a non-toxic anion.

These new compounds are useful as antispasmodic agents.

These quaternary ammonium salts are prepared by reacting alkyl or aralkyl esters of inorganic acids or certain strong organic acids such as sulfonic acids of the formula R'X with a nitrile of the formula CoHn where R, Y and N=B have the meanings given hereinabove. Such salt-forming substances of the formula R'X include methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl chloride, propyl bromide, propyl iodide, isopropyl bromide, butyl ch1oride, butyl bromide, isobutyl bromide, sec.- butyl bromide, n-amyl bromide, n-hexyl chloride, benzyl chloride, benzyl bromide, methyl sulfate, ethyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, etc., which will react directly with any nitrile of the above formula to give respectively the methochloride, methobromide, methiodide, ethochloride, ethobromide, ethiodide, propochloride, propobromide, propiodide, isopropobromide, butochloride, butobromide, isobutobromide, sec.-butobromide, n-amobromide, nhexochloride, benzochloride, benzobromide, methosuliate, ethosulfate, methobenzenesulfonate, metho-p-toluenesulfonate, etc.

The quaternary ammonium salts are generally prepared by warming the free base with an excess of the salt-forming ester, RX, in an inert organic medium such as benzene or ether. The quaternary ammonium salt will separate, usually as a crystalline product, or can be made to precipitate by the addition of other solvents or by concentration of the solution.

Alternatively, it is possible by use of metathetical reactions to replace the anion of a quaternary by a different anion without reconversion to the free base. This is usually effected by treatment of a solution of the quaternary, QX, with silver oxide (hydroxide). The silver salt, AgX, is precipitated leaving in solution the quaternary hydroxide, QOH. It is prerequisite, of course, that the salt AgX be insoluble in water. The quaternary hydroxide may then be neutralized .with the appropriate acid to give any desired salt. For example, methiodides are generally easier to prepare by direct addition than methochlorides. Methyl iodide reacts more readily and is more convenient to use than methyl chloride. However, the methochloride may be readily prepared from the methiodide by the method just described. Treatment of a solution of the methiodide with silver oxide precipitates silver iodide leaving a, solution of the quaternary hydroxide. Neutralization of this solution with hydrochloric acid gives the methochloride which can be obtained byv concentration of the solution.

The intermediate nitriles are prepared by effecting successive alkylations of phenylacetonitrile (benzyl cyanide). Alkylation of phenyl-- acetonitrile with a cycloalkyl, alkyl, or alkenyl halide in the presence of a strong metalating agent such as sodium amide or sodium hydride gives a compound of the formula (C6H5)RCHCN- This may be further alkylated with a tertiaryaminoalkyl halide to give NaNHa cng-on-on,

halide, cyclohexyl halide, etc. The halogen atoms may be chlorine, bromine or iodine.

When it is desired to introduce an alkenyl group which has a double bond in the vinyl position with respect to the alpha-carbon of the substituted acetonltrile, a variation in synthesis must be employed because of the unreactivity of COHiCHiCN o=cHcN cn,

enn i-0N cmcnom NaNHa (k lcNCHaCHgCl -----0 CH;- C-CH:

H ClHl-CHICHaN CHli The alpha-substituent of the substituted phenylacetonitrile, --Y-N=B, is introduced by alkylation using the halide, HalY-N=B. Y represents a two-carbon chain which may bear alkyl substituents, such as one or more methyl or ethyl radicals, on either or both carbon atoms of the chain. It includes alkylene chains of the type where X represents hydrogen or lower alkyl radicals. Such alkylene radicals having the free valence bonds only on adjacent carbon atoms may be termed alpha, beta-alkylene radicals, alpha indicating one of the carbon atoms in the above formula and beta indicating the adjacent carbon atom. The term alpha,beta distinguishes alkylene radicals of the above type from those in which the free valence bonds are not on adjacent carbon atoms of the radicals. The grouping N=B represents a tertiary-amino radical which may be dialkylamino, the two alkyl groups being the same or diflerent, or a saturated 5-6, membered heterocyclic radical such as piperidyl, pyrrolidyl, morpholinyl or thiomoraminoethyl chloride, beta (N piperidyl) ethyl .chloride, beta-(N-pyrrolidyl) ethyl chloride, beta- (IN-morpholinyl) ethyl chloride, etc.

When used, for example, to alkylate isobutylphenylacetonitrile, the above named aminoalkyl halides give the following nitriles respectively: isobutyl-beta-dimethylaminoethyl phenylacetonitrlle, isobutyl beta ethylmethylaminoethylphenylacetonitrile, isobutyl-betadiethylaminoethyl-phenylacetonitrile, isobutyl-(alpha-methyl-beta diethylaminolethyl phenylacetonitrile, isobutylbeta-dipropylaminoethyl phenylacetohitrile, isobutyl-beta-dibutylaminoethylphenylacetonitrile, isobutyl beta-(N piperidyl) ethylphenylacetonitrile, isobutyl-beta-(N-pyrrolidyl) ethyl-phenylacetonitrile, and isobutyl-(N-morpholinyl) ethyl-phenylacetonitrile.

The quaternary ammonium salts of my invention are prepared by addition of alkyl or aralkyl esters, described earlier, to the basic nitriles. The nitriles named in the preceding paragraph may be employed, for example, as follows: isobutyl-beta-dimethylaminoethyl phenylacetonitrile reacts with methyl chloride to give (Ii-cyano- 3-phenyl-3-isobutyl) propyl-trimethylammonium chloride; isobutyl-beta ethylmethylaminoethyl phenylacetonitrile reacts with methyl bromide to give (3-cyano-3-phenyl-3-isobutyl)propyl-ethyldimethylammonium bromide; isobutyl-beta-diethylaminoethyl-phenylacetonitrile reacts with methyl iodide to give (3-cyano-3-phenyl-3-isobutyl) propyl-diethyl methylammonium iodide; isobutyl (alphamethyl-beta-diethylamino) propyl-phenylacetonitrile reacts with ethyl bromide to give (l,2-dimethyl-3-cyano-3-phenyl-3isobutyl) propyl-triethylammonium bromide; isobutylbeta-dipropylaminoethyl phenylacetonitrile reacts with propyl bromide to give (3-cyano-3- phenyl 3 isobutyl) propyl-tripropylammonium bromide; isobutylbeta-dibutylaminoethyl-phenylacetonitrile reacts with n-hexyl bromide to give (3-cyano-3 phenyl-3-y-isobutyl) propyl-dibutyl-nhexylammonium bromide; isobutyl-beta-(N-piperidyDpropylphenylacetonitrile reacts with benzyl chloride to give N-(l-methyl-3-'cyano-3- phenyl 3 isobutyl) propyl benzylpiperidinium chloride; isobutyl beta (N pyrrolidyl) ethylphenylacetonitrile reacts with p-methylbenzyl bromide to give N-(3-cyano-3phenyl-S-isobutyl) propyl p methylbenzylpyrrolidinium bromide; and isobutyl-(N-morpholinyl)ethyl-phenylacetonitrile reacts with methyl iodide to give N- (3cyano-3-phenyl-3-isobutyl) propyl-methylmorpholinium iodide.

The following examples will illustrate my invention more completely but should not be construed as a limitation thereto.

EXAMPLE 1 (a) Phenylisobutylacetonitrile.Benzyl cyanide (293 g.) was added gradually to a stirred suspension of 115 g. of sodium amide in 250 cc. of dry benzene at 40-50 C. The mixture was stirred at 50 C. for one and one-half hours, cooled to 25 C., and 343 g. of isobutyl bromide was added. After heating for an additional two hours at 65 C., the mixture was cooled and the excess sodium amide was hydrolized by addition of alcohol and water. The organic layer was separated and washed with dilute hydrochloric acid and water and dried over anhydrous sodium sulfate. The product was then fractionated and refractionated through a heated column, packed with glass helices, and the product, B. P. -90 C. (0.5 mm.), n =1.4978-85, was collected.

Phenylisobutwl (N-piperidylethyD-acetonitrile.

CHr-CHCH H: CHr-J3-CH1CHINC5H" A stirred suspension of 18 g. of sodium amide in a solution of 26 g. of phenylisobutylacetonitrile in 200 cc. of dry. benzene was heated to 65 C. for a few minutes. The mixture was then cooled to about 30 C., and 27.6 g. of N-piperidylethyl chloride hydrochloride was added. After refluxing for two hours, the mixture was cooled and the excess sodium amide was hydrolyzed by addition of alcohol and water. The organic layer was separated and washed with water and dried over anhydrous sodium sulfate. The product was distilled at reduced pressure giving 34 g.

N CH:

NC5H10 was prepared by heating phenylisobutyl-(N- piperidylethyl)-acetonitrile with an excess of methyl iodide in benzene solution. The desired compound crystallized upon cooling and was collected by filtration and recrystallized from ethyl acetate. It had the M. P. 171-173 C.

Anal. calcd. for CzoHsrNzIt C, 56.33; H, 7.33; I, 29.77. Found: C, 56.55; H, 7.33; I, 29.62.

EXAMPLE 2 (a) Phenylcyclohexyldiethulaminoethylacetonitrile.

A stirred suspension of 48.4 g. of sodium amide in a. solution of 207.3 g. of phenycyclohexylacetonitrile (Organic Syntheses 25, in 200 cc. of dry benzene, was heated to 65 C. for a few minutes. The mixture was then cooled to about C. and 144.4 g. of N-diethylaminoethyl chlorlde was added. After refluxing for two hours, the mixture was cooled and the excess sodium amide was hydrolyzed by addition of alcohol and water. The organic layer was separated and washed with water and dried over anhydrous sodium sulfate. The product was distilled at reduced pressure giving 256 g. of phenylcyclohexyldiethylaminoethylacetonitrile, B. P. 174- 182 C. (2 mm.); n =1.5187.

Its hydrochloride had the M. P. 157-158 C.

Anal. calcd. for CzoHnNzCl: N, 8.37; Cl. 10.59. Found: N, 8.36; Cl, 10.60.

6 (b) (3-cyano-J-PhenIII-J-cfldoWI)flfmldiethyl-methylammonium iodide was prepared by heating phenylcyclohexyldiethylaminoethylacetonitrile with an excess of methyl iodide in benzene solution. It had the M. P. 169-170 C.

Anal. calcd. for C21HJ3N2I: C, 57.26; H, 7.55;

N, 6.36 I, 28.82. Found: C, 57.09; H, 7.34; N,

EXAMPLE 3 l (a) Phenylisobutyldiethylaminoethulacetonitrile CHr-CH-CH;

Ha CsHr--:-CH1CH1N(C:HI)!

was prepared by a method similar to that described in Example 2, part (a). The reaction of 86.7 g. of phenylisobutylacetonitrile (Example 1, part a), 65 g. of diethylaminoethyl chloride and g. of sodium amide gave 110 g. of phenylisobutyldiethylaminoethylacetonitrile, B. P. 114- 118" C. (0.05 mm.) 15 1-14960.

Its hydrochloride had the M. P. 133-l34 C.

Anal. calcd. for CwHzsNzCl: N, 9.07; Cl, 11.48.

Found: N, 9.09; Cl, 11.42.

(b) (3 cyano 3 phenyl 3 isobutyl) propuldiethyl-methylammonium iodide was prepared by heating phenylisobutyldiethylaminoethylacetonitrile with an excess of methyl iodide in benzene solution. It had the M. P. 155.5- 157 C.

Anal. calcd. for CiaHnNaI: N, 6.76; I, 30.63 Found: N, 6.72; I, 30.60.

(c) (3 cyano 3 phenyl 3 isobutyl) propuldiethy" enzylammonium chloride N(C2H5)| CuHsCHz Cl A mixture of 19.1 g. of phenylisobutyldiethylaminoethylacetonitrile, 9.9 g. of benzyl chloride and 75 ml. of ethyl acetate was heated on a steam bath for three hours. Then part of the ethyl acetate was evaporated and ether added whereupon a crystalline solid precipitated. This suspension was collected by filtration, and the resulting benzochloride of phenylisobutyldiethylaminoethylacetonitrile was recrystallized from a methanol-ether mixture giving 6.7 g., M. P. 162- 164 C. (uncorrected).

7 (d) (3 cyano 3 phenyl 3 isobutyl) propyltri'ethylammonium bromide s s cHmoHcm-e-cm N CH:

N-(CIHI)2 dZHl Br A mixtur of 19.1 g. of the nitrile and 33 g. of ethyl bromide was heated at about 50 C. for ten days. The excess of ethyl bromide was evaporated and the residue was recrystallized from an acetone-ether mixture giving the ethobromide of phenylisobutyldiethylamin'oethylacetonitrile, M. P. 135.5-13'7" C. (uncorr.)

EXAMPLE 4 (a) PhenylisobutyZdim ethylaminoethylacetonitrile om-cH-cm H2 CeHr-(E- CH: CH2N( CH3):

was prepared by a method similar to that described in Example 2, part (a). The reaction of 86.7 g. of phenylisobutylacetonitrile, 54 g. of dimethylaminoethyl chloride and 30 g. of sodium amide gave 71.6 g. of phenylisobutyldimethylaminoethylacetonitrile, B. P. 112-120 C. (0.4 mm.); n =1.5020.

Its hydrochloride had the M. P. 242-243" C.

Anal. calcd. for C16H25N2C1 C, 68.43; H, 8.97;

Cl, 12.63. Found: C, 68.56; H, 9.07; C1, 1253.

( b) (3 cyano 3 phenyl 3 isobutyl) propyltrimethylammonium iodide CaHs cHmcHcm- CH,

N CH:

N- cm CH3 I was prepared by heating phenylisobutyldimethylaminoethylacetonitrile with an excess of methyl iodide in benzene solution. It had the M. P. 150.5-

Anal. calcd. for C17H27N2I2 N, 7.25; I, 32.85.

Found: N, 7.14; I, 33.25.

EXAMPLE 5 (a) Phenyl (2 methyl 1 propenyl) (N- piperz'dylethyl) acetonitrile was prepared by a method similar to that described in Example 1, part (b). The reaction of 85.6 g. of isobutylidene-phenlyacetonitrile [Murray and Cloke, J. Am. Chem. Soc. 58, 2016 (1936) l, 2 g. of piperidylethyl chloride hydrochloride and g. of sodium amide gave 106 g. (75%) of phenyl (2 methyl 1 propenyl) (N piperidylethyD-acetonitrile, B. P. 136-139 C. (0.05 mm.); n =1.5260.

Its hydrochloride had the M. P. 203-204. 5 C.

Anal. calcd. for CmHmNzCl: N, 8.79; Cl, 11.12. Found: N, 8.60; C1, 11.12.

I claim: 1. A quaternary ammonium salt of the formula CaHs lN Y

LN=B x.

wherein R is a member of the group consisting of alkyl and alkenyl radicals of 4-6 carbon atoms and 5-6 membered cycloalkyl radicals, R is a hydrocarbon group selected from the class consisting of lower alkyl and phenyl-lower alkyl radicals, Y is a lower alpha, beta-alkylene radical, N=B is a member of the group consisting of dialkylamino, piperidino, pyrrolidino and morpholino, and X is a non-toxic anion.

2. A'quaternary ammonium'salt of the formula wherein R is a 5-6 membered cycloalkyl radical, N=B is a dialkylamino group, R is a lower alkyl group and X is a non-toxic anion.

3. A quaternary ammonium salt of the formula CsHl wherein R is a 5-6 membered cycloalkyl radical,

N=B is a piperidino group, R is a lower alkyl group and X is a non-toxic anion.

4. A quaternary ammonium salt of the formula CIR;

R- CH:

wherein R is an alkyl radical of 4-6 carbon atoms. N=B is a dialkylamino group, R is a lower alkyl group and X is a non-toxic anion.

5. A quaternary ammonium salt of the formula 00H R-C-CH:

9 wherein R is an alkyl radical of 46 carbon atoms. N=B is a piperidino group, R is a lower alkyl group and X is a non-toxic anion.

6. (3'- cyano 3 phenyl 3 isobutyDpropyl methylpipcridinium iodide having the formula JVHCH2CCHQ(VHQN -H (W o I. email 7. (3 cyano 3 phenyl 3 isobutyl) propyl diethylmethylammonium iodide having the formula 8. The process for preparing a quaternary ammonium salt of the formula wherein R is a member of the group consisting of alkyl and alkenyl radicals of 46 carbon atoms and 5-6 membered cycloalkyl radicals, Y is a lower alpha,beta-alkylene radical, R is a hydrocarbon group selected from the group consisting of lower alkyl and phenyl-lower alkyl radicals, N=B is a member of the group consisting of dialkylamino, piperidino, pyrrolidino and morpholino, and X is a non-toxic anion; which comprisestreating a nitrile of the formula with a compound R)! in an inert organic solvent.

9. The process for preparing a quaternary ammonium salt of the formula where R is an alkyl group of 4-6 carbon atoms, R is a lower alkyl group, N=B is a dialkylamino group and X is a non-toxic anion; which comprises treating a nitrile of the formula CIHB R- CH:CHzN=B with a compound R)! in an inert organic solvent.

10. The process for preparing a quaternary ammonium salt of the formula R x cmom wherein R is an alkenyl radical of 4-6 carbon atoms, R is a lower alkyl group and X is a nontoxic anion.

14. (3 cyano 3 phenyl 3 cyclohexyl) propyl diethylmethylammonium iodide having the formula 15. [3 cyano 3 phenyl 3 -(2 methyl 1' propenyDlpropyl methylpiperidinium iodide having the formula CH3 CeHg I CHzCH:

=CH- CHrCHzN \CH: 43H: N C 3 CHICHg ARLO WAYNE BUDDY.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,032,097 Piggott et al. Feb. 25, 1936 2,109,024 Holzach et al. Feb. 27, 1938 2,113,606 Taub et a1. Apr. 12, 1938 2,405,555 Bergel et a1. Aug. 13, 1946 2,446,804 Bergel et a1. Aug. 10, 1948 FOREIGN PATENTS Number Country Date 728,241 France Dec. 14, 1931 884,569 France July 30, 1942 OTHER REFERENCES Cohen et a1., Jour. Chem. Soc. (London). vol. 107 (1915), pages 901 and 902.

Eisleb, Berichte Der Deu Chem. vol. 74B (1941), p. 1442. 

1. A QUATERNARY AMMONIUM SALT OF THE FORMULA 